Search

Abstract Background Hyperhomocysteinemia (HHcy) causes increased oxidative stress and is an independent risk factor for cardiovascular disease. Oxidative stress is now believed to be a major contributory factor in the development of non alcoholic fatty liver disease, the most common liver disorder worldwide. In this study, the changes which occur in homocysteine (Hcy) metabolism in high fat-diet induced non alcoholic fatty liver disease (NAFLD) in rats were investigated. Methods and results After feeding rats a standard low fat diet (control) or a high fat diet (57% metabolisable energy as fat) for 18 weeks, the concentration of homocysteine in the plasma was significantly raised while that of cysteine was lowered in the high fat as compared to the control diet fed animals. The hepatic activities of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGS), the enzymes responsible for the breakdown of homocysteine to cysteine via the transsulphuration pathway in the liver, were also significantly reduced in the high fat-fed group. Conclusions These results indicate that high fat diet-induced NAFLD in rats is associated with increased plasma Hcy levels caused by down-regulation of hepatic CBS and CGL activity. Thus, HHcy occurs at an early stage in high fat diet-induced NAFLD and is likely to contribute to the increased risk of cardiovascular disease associated with the condition.

Abstract Dysregulated inflammation in cystic fibrosis (CF) is attributed to an altered production of inflammatory mediators derived from polyunsaturated lipids. In comparison to the arachidonic acid (AA) cascade, little is known about the modulation of docosahexaenoic acid (DHA) membrane release. We compared data on neutrophil DHA- and AA- release from both control (CT) and patients with CF using [3H]AA or [14C]DHA as a markers for, respectively, AA and DHA- release. Granulocyte-macrophage-colony stimulating factor stimulated DHA release from CT, but not CF, neutrophils. Comparison showed that both [14C]DHA and [3H]AA liberated after stimulation was higher in CT than in CF neutrophils. Since bioactive mediators derived from DHA are resolving factors and those derived from AA are both pro- and anti- inflammatory, these results suggest that CF is associated with a reduction of the release of PUFA-precursors of lipooxygenated resolving mediators. This leads to the hypothesis that defects in the resolving factors production could contribute to the inflammatory dysregulated processes in CF. Furthermore, the methodology used may help to improve knowledge on the regulation and resolution of inflammation.

Mesenchymal stromal cells (MSCs), multipotent cells present in tissues throughout the body, can reconstitute adipogenic, osteogenic and chondrogenic tissues, but are also of great interest as mediators of immune modulation and suppression. MSCs are able to improve transplant engraftment, treat graft versus host disease and suppress T cell responses and therefore have great potential as therapeutic agents. Their immune modulatory capacity is mediated through both cell-to-cell contact and cytokine secretion, but it is becoming clear that extracellular vesicles (EV) produced by MSC also possess immunomodulatory properties. These vesicles are easy to prepare and store, do not carry nuclear material and cannot form tumours, and therefore also represent a highly desirable therapeutic agent. This review outlines the formation and characterisation of extracellular vesicles, the reported function of MSC-EVs in vitro and in vivo, and addresses some of the emerging issues with nomenclature, EV therapeutic dose and tissue source. The development of GMP-grade production protocols and effective characterisation of MSC extracellular vesicles is essential to their successful use as immune modulating therapeutic agents, and this review outlines the current status of the research in this area., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Background: Clinic-based effectiveness studies of sleep-disordered breathing (SDB) treatment in reducing BP in resistant hypertension (RHTN) vs non-RHTN are sparse. We hypothesize that CPAP use in SDB reduces BP significantly in RHTN and non-RHTN in a large clinic-based cohort., Methods: Electronic medical records were reviewed in patients with SDB and comorbid RHTN and non-RHTN for CPAP therapy initiation (baseline) and subsequent visits. We estimated generalizable BP changes from multivariable mixed-effects linear models for systolic BP (SBP), diastolic BP, and mean arterial pressure, adjusting for RHTN status, age, sex, race, BMI, cardiac history, and diabetes and repeated measure correlation., Results: Of 894 patients, 130 (15%) had RHTN at baseline (age, 58 ± 12 years; 52% men; BMI, 36 ± 9 kg/m(2)). Patients with RHTN had significantly higher BP overall (P < .001), most notably for SBP (6.9 mm Hg; 95% CI, 3.84, 9.94). In the year following CPAP initiation, improvements in BP indexes did not generally differ based on RHTN status in which RHTN status was a fixed effect. However, there was a significant decrease in SBP (3.08 mm Hg; 95% CI, 1.79, 4.37), diastolic BP (2.28; 95% CI, 1.56, 3.00), and mean arterial pressure (2.54 mm Hg; 95% CI, 1.73, 3.36) in both groups., Conclusions: In this clinic-based effectiveness study involving patients closely followed for BP control, a significant reduction of BP measures (strongest for SBP) was observed in response to CPAP which was similar in RHTN and non-RHTN groups thus informing expected clinical CPAP treatment response., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Renal sympathetic denervation has shown promise in treating hypertension resistant to drug therapy. This procedure lowers blood pressure via targeted attenuation of renal sympathetic tone, and it has a favorable safety profile. But although there is reason for cautious optimism, we should keep in mind that the mechanisms of hypertension are complex and multifactorial, and further study of this novel therapy and its long-term effects is needed.

Objective: To assess the value of adrenal mass absolute growth, growth rate, and percentage growth rate on serial imaging for distinguishing benign from malignant adrenal masses., Methods: We retrospectively reviewed the Cleveland Clinic medical record data on 136 adrenalectomies or biopsies in 132 patients with 2 imaging studies performed more than 2 months apart (during 1997 to 2008)., Results: There were 111 benign (81.6%) and 25 malignant (18.4%) adrenal masses. With use of receiver operating characteristic curve analysis, all 3 aforementioned growth measures showed similar levels of discrimination for the entire study group as well as for the subgroups with 3 to 12 months of follow-up (n = 75 masses) and noncontrast computed tomography Hounsfield units >10 or not reported (n = 111 masses). After adjustment for other factors, the 3 growth measures remained statistically significant predictors of a malignant tumor. The absolute growth cutoff value of 0.8 cm had the highest sum of sensitivity and specificity of 72% and 81.1%, respectively. We could not identify an adrenal mass growth cutoff value to provide 100% sensitivity or specificity to confirm or exclude the presence of a malignant lesion. In 3 patients with metastatic lesions, no growth or a decrease in mass size during a period of 4 to 36 months was observed., Conclusion: In this study, the largest with surgical histopathology findings as the "gold standard" for diagnosis, change in adrenal mass size was a significant predictor of a malignant tumor. Nevertheless, we could not identify an adrenal mass growth cutoff value for reliable confirmation or exclusion of a malignant lesion. Change in adrenal mass size should be used in conjunction with other imaging and clinical characteristics when surgical resection is being considered.

We report on the efficacy and safety of short-term administration of temozolomide, an inhibitor of nucleoside incorporation, in a 60-year-old woman with widespread hepatic metastases from a malignant paraganglioma. Temozolomide was orally administered in daily doses of 250 mg on days 1 to 5 and repeated every 28 days for five cycles. Clinical improvement was immediate and associated with weight gain, and further reduction in blood pressure without ortho-static intolerance. In addition, abnormal hepatic function was normalized and catecholamine production was significantly reduced. Except for mild nausea, adverse effects were virtually absent. Bone marrow function, renal function, and serum electrolytes remained normal; hemoglobin remained above 9 g/dl through treatment. The platelet count decreased but not to clinically meaningful levels. These responses allowed for a surgical debulking procedure to be performed safely without complications. The results suggest that temozolomide may be useful in presurgical preparation of patients with pheochromocytoma especially in those with widespread metastatic disease and poor physical condition. However, the present findings need confirmation in a larger study and the role of temozolomide in the long-term treatment of malignant paraganglioma/pheochromocytoma remains to be established.

Radiological characterization of an adrenal tumor as adenoma may decrease the need for follow-up imaging studies, biopsies, and unnecessary adrenalectomies. We retrospectively reviewed 299 adrenalectomies in 290 patients at Cleveland Clinic Foundation over a recent 5-yr period to assess the value of noncontrast Hounsfield units (HU) in characterizing whether an adrenal mass is adenoma or nonadenoma. The mean (+/- SD) HU value for the adrenocortical adenoma/hyperplasia group was 16.2 +/- 13.6 and significantly lower (P < 0.0001) than primary adrenocortical cancers (36.9 +/- 4.1), metastases (39.2 +/- 15.2), and pheochromocytomas (38.6 +/- 8.2). The sensitivity and specificity for 10- and 20-HU cutoff values to differentiate adenomas/hyperplasias from nonadenomas were 40.5 and 100% and 58.2 and 96.9%, respectively. The size of the adrenal tumor had less value with only 40.7 and 81.3% sensitivity and 94.7 and 61.4% specificity for 2- and 4-cm cutoff values. A combination of less than or equal to 4-cm adrenal mass size and noncontrast computed tomography HU less than or equal to 20 had 42.1% sensitivity and 100% specificity. Our study, the largest with surgical histopathology as the gold standard for diagnosis, supports a noncontrast computed tomography attenuation value of 10 HU as a safe cutoff value to differentiate adrenal adenomas/hyperplasias from nonadenomas.

Pheochromocytomas (pheo) cause the most dramatic, life-threatening crises in all of endocrinology. A proper screening for pheo must be performed in any patient who has: 1) episodic headaches, tachycardia, and diaphoresis; 2) family history of pheo or multiple endocrine neoplasia; 3) incidental suprarenal mass; 4) paroxysms of tachyarrhythmias or hypertension; 5) adverse cardiovascular responses to anesthetic agents, histamine, phenothiazine, tricyclic antidepressants, etc); and 6) spells occurring during exercise, straining, etc. The key to diagnosing pheo is to suspect it, then to confirm it. Early recognition of its presence is critical to avoiding significant morbidity and mortality. Once suspected, the diagnosis can be confirmed with biochemical testing in virtually all patients. The combination of resting plasma catecholamines > or =2000 pg/mL and urinary metanephrines > or =1.8 mg/24 h has a diagnostic accuracy of 98% in both sporadic and hereditary pheos. When available, measurement of plasma free metanephrines should be performed especially in hereditary pheos. Provocative (glucagon) and suppression tests (clonidine) may be necessary when baseline measurements are inconclusive. CT and MRI are equally sensitive for localization (98% and 100%, respectively), but have lower specificities (70% and 67%). MIBG is 100% specific, but less sensitive (78%). The availability of various medical (selective alpha-1- and beta-adrenergic receptor antagonists, calcium channel blockers) and surgical modalities have made successful management more promising than ever before.

This review provides current understanding of the pathophysiology of pheochromocytoma and the wide range of associated clinical manifestations that have led to earlier recognition of the disease. In addition, it reviews optimal screening methods and localization techniques that have enhanced the clinician's ability to make the diagnosis with greater certainty. This article will also discuss alternative antihypertensive regimens and innovative anesthetic and surgical procedures that have made successful management more promising than ever before. Areas requiring further development include additional clinical experience with the measurement of plasma metanephrines that have been shown to have high sensitivity and specificity in the diagnosis of sporadic and familial pheochromocytoma, optimizing cost effectiveness of diagnostic imaging, improving the ability to predict and treat malignant pheochromocytoma, and elucidating not only the surgical approach but, perhaps with rapid advances in molecular genetics, ways of preventing familial pheochromocytoma.

Recent preclinical and clinical studies indicate that aldosterone, independent of angiotensin II and elevated blood pressure, may play a role in health and disease. In addition to its role in fluid and electrolyte balance and circulatory homeostasis, more recent studies have identified aldosterone as a critical mediator of vascular damage. In animal studies, aldosterone is implicated in cardiac and vascular fibrosis, renal disease, and cerebrovascular damage. These lesions are prevented by specific aldosterone receptor blockade. In clinical studies, aldosterone receptor antagonism is associated with decreased hospitalization, symptomatology, and mortality, and improvement of endothelial dysfunction in patients with chronic heart failure. A better understanding of aldosterone's actions in nonepithelial tissues should pave the way to better protection of organs at risk such as the kidneys, heart, and brain.

Introduction: To describe the technique of transperitoneal laparoscopic bilateral synchronous partial adrenalectomy in a patient with bilateral adrenal pheochromocytoma., Technical Considerations: An 81-year-old woman with bilateral adrenal pheochromocytoma underwent bilateral laparoscopic partial adrenalectomy. A three-port transperitoneal approach was used for each side, with an additional port for liver retraction during right partial adrenalectomy. Laparoscopic flexible ultrasonography was invaluable for localizing the adrenal tumor and for precise planning of the line of excision. The right main adrenal vein was preserved. Dissection and enucleation of the adrenal tumor and parenchymal hemostasis was achieved effectively using a harmonic scalpel. The total operative time was 2 and 2.5 hours for the left and right adrenal gland, respectively. No major intraoperative hemodynamic instability was noted. The total blood loss was 150 mL, and the hospital stay was 4 days. Pathologic examination confirmed bilateral adrenal pheochromocytoma., Conclusions: Laparoscopic partial adrenalectomy for pheochromocytoma is safe and technically feasible. Intraoperative ultrasonography is helpful to accurately plan resection of the tumor. If tumor location permits, the main adrenal vein should be preserved to ensure adequate vascularity for the adrenal remnant.

Introduction: Remote robotic telemanipulators have been recently used in performing laparoscopic urologic procedures, both in the laboratory and in clinical practice. We present, to our knowledge, the initial 2 cases of robotic-assisted laparoscopic adrenalectomy in humans., Technical Considerations: Robotic-assisted laparoscopic adrenalectomy (one right, one left) was performed in 2 patients with an adrenal tumor (one nonfunctional, one pheochromocytoma). Patient age was 81 and 47 years, and tumor size was 4.5 and 3 cm, respectively. Both cases were performed transperitoneally using the da Vinci Robotic Surgical System. Robotic-assisted laparoscopic adrenalectomy was successful in both cases without conversion to conventional laparoscopy or open surgery. The operative time was 110 and 165 minutes, the blood loss was 50 and 100 mL, and the hospital stay was 2 and 3 days. No intraoperative or postoperative complications occurred., Conclusions: Robotic-assisted laparoscopic adrenalectomy is technically feasible. With increasing experience and refinement in the technology, the role of robotics in urologic laparoscopy is likely to expand.

Pheochromocytoma and paragangliomas are rare tumors of chromaffin tissue that secrete catecholamines either intermittently or continuously, producing hypertension with a constellation of symptoms and signs that can be frightening to the patient and that continue to provide perplexing problems for clinicians. With surgical treatment, symptoms will be relieved and hypertension normalized or ameliorated for patients who do not have malignant tumors. Appropriate antihypertensive drugs are used to manage hypertension, to control associated cardiovascular symptoms, and to prepare patients for operation. The question debated most often regarding medical therapy of pheochromocytoma is whether antihypertensive treatment regimens other than nonspecific alpha-blockade are just as effective and safe. Understanding the pathophysiologic mechanisms that sustain the hypertension and the pharmacology of antihypertensive agents allows better selection of antihypertensive therapy.

Pheochromocytomas cause the most dramatic, life-threatening crises in all of endocrinology. Pheochromocytoma is an explosive clinical syndrome characterized by severe hypertension associated with cardiac complications, hypotension, or even shock and sudden death. The key to diagnosing pheochromocytoma is to suspect it, then confirm it. The cases reported in this review illustrate how the diagnosis can be easily missed and definitive treatment delayed. An appreciation of the wide range of clinical manifestations, based on clear understanding of the mechanisms of catecholamine action and the pathophysiology of pheochromocytoma, and the availability of simple and accurate diagnostic tests should lead to earlier detection of these tumors. Advances in localization techniques and availability of various treatment modalities have made successful management more promising than ever before.

Most forms of primary aldosteronism are surgically correctable. However, when surgery is not appropriate, medical management is just as effective in correcting the pathophysiologic abnormalities due to aldosterone excess. A prerequisite for the rational medical management of primary aldosteronism is an understanding of the mechanisms that sustain hypertension. Primary aldosteronism can be associated with severe and resistant hypertension, and persistent hypervolemia is the primary reason for resistance to therapy. Patients with overriding comorbidities or strong preferences have been medically treated over the intermediate term of 5 to 7 years without evidence of escape or evidence of malignant transformation of adrenal adenomas.

To our knowledge, laparoscopic right adrenalectomy has not been previously reported after orthotopic liver transplantation. The aim of this report is to demonstrate the feasibility of the laparoscopic approach in this technically challenging situation, and to outline some considerations unique to this clinical setting.

Purpose: Physiologically significant renal artery lesions in the presence of a pheochromocytoma comprise a confounding factor which may impact on the hypertension cure following excision of the pheochromocytoma. We present 10 cases of these dual lesions and review the literature on this entity., Materials and Methods: From 1952 to 1999, 269 patients were diagnosed with pheochromocytoma at our institution. Hospital charts of these patients were reviewed retrospectively to identify those with coexisting renal artery stenosis. A Medline search was performed to review the available literature., Results: Of the 269 patients with pheochromocytoma 10 (3. 7%) had coexisting renal artery lesions, including renal artery stenosis in 8, renal artery aneurysm in 1 and postangiographic dissection occlusion in 1. Pheochromocytoma was adrenal in 8 cases and ectopic in 2. Of the patients 9 have been treated to date by adrenalectomy in 4, nephroadrenalectomy in 3, adrenalectomy plus lysis of renal artery adhesions in 1 and adrenalectomy plus renal autotransplantation with bench repair in 1. Both lesions were diagnosed preoperatively in 9 cases and a hypovascular adrenal lesion was missed preoperatively in 1. A review of literature revealed a total of 87 cases of coexisting pheochromocytoma and renal artery lesions., Conclusions: There are multiple mechanisms that can lead to renal artery stenosis and pheochromocytoma. A high index of suspicion is necessary to enable both entities to be diagnosed preoperatively and allow proper planning of surgical therapy. Incomplete diagnosis may lead to persistent hypertension postoperatively.

Background and Purpose: Laparoscopic adrenalectomy has emerged as the standard of care at many centers for small surgical adrenal masses. However, the role of laparoscopic adrenalectomy in the treatment of large adrenal masses has not been specifically addressed. Our aim was to evaluate the outcome of laparoscopic v open adrenalectomy for large-volume (> or =5 cm) adrenal masses and to compare laparoscopic adrenalectomy for large- and small-volume (<5 cm) masses., Patients and Methods: Data from 14 patients with large adrenal masses undergoing laparoscopic adrenalectomy between February 1998 and March 1999 (Group I) were retrospectively compared with 14 contemporary large-volume open adrenalectomies between December 1992 and May 1998 (Group II) and 45 small-volume laparoscopic adrenalectomies between July 1997 and November 1998 (Group III)., Results: In Group I and Group II, the mean surgical time (205 min v 216 min) and blood loss (400 mL v 584 mL) were similar. Although the mean adrenal size was also comparable (8 cm v 7.8 cm), the specimen weight of the en bloc adrenal gland and periadrenal fat was greater in Group I (168 g v 106 g). The hospital stay was shorter in Group I (2.4 days v 7.7 days). Minor complications occurred in 21.4% of Group I and 50% of Group II patients. On comparing Group I and Group III (laparoscopic <5 cm), Group I had larger specimen weight (168 g v 51.4 g), longer surgical time (205 min v 158 min), greater blood loss (400 mL v 113 mL), longer hospital stay (2.4 days v 1.5 days), a higher complication rate (21.4% v 8.9%), and a higher incidence of open surgical conversion (14.3% v 2.2%). Over a mean follow-up of 9.9 months, no local or port-site recurrences have been noted in Group I., Conclusions: Laparoscopic adrenalectomy for large-volume adrenal masses is technically feasible and seems to replicate open surgical oncologic principles of achieving a wide-margin, en bloc excision of the adrenal gland and periadrenal fat. Successful laparoscopic resection is not impacted by the large size of the adrenal mass per se but rather by the presence of local invasion and poorly defined tissue planes that may be encountered in adrenal malignancy. As such, laparoscopic adrenalectomy for large masses should be attempted only by experienced laparoscopic surgeons and then with a low threshold for open conversion.

Purpose: To our knowledge we report the initial experience with outpatient, same day laparoscopic adrenalectomy., Materials and Methods: Nine select patients were entered into our ambulatory adrenalectomy protocol. Each patient fulfilled certain preoperative and postoperative inclusion criteria, including informed consent, age 70 years or older, body mass index 40 or less, adrenal tumor less than 5 cm., no pheochromocytoma, uncomplicated laparoscopic surgery that was completed by 12 p.m., perioperative hemodynamic stability and pain control by oral analgesics., Results: All 9 patients successfully underwent outpatient laparoscopic adrenalectomy. Average patient age was 53 years and average adrenal tumor size was 2 cm. Mean surgical time was 2.3 hours and mean blood loss was 53 ml. The diagnosis was aldosteroma in 7 cases, enlarging adenoma in 1 and myelolipoma in 1. Average postoperative hospital stay was 416 minutes (range 300 to 570). Postoperative analgesia comprised 6 mg. morphine sulfate and 32 mg. ketorolac. The only complication was a local abscess requiring delayed drainage at 2 weeks. No other patient was rehospitalized for any reason. A followup questionnaire survey revealed excellent patient satisfaction., Conclusions: To our knowledge we report the initial series of outpatient laparoscopic excision of a solid organ, the adrenal gland. Ambulatory adrenalectomy is feasible and safe, and results in high patient satisfaction. However, ambulatory adrenalectomy should be restricted to highly select patients and performed by minimally invasive surgeons who have considerable experience with laparoscopic adrenal surgery.

Objectives: To compare the anesthetic aspects and intraoperative hemodynamic data and immediate postoperative outcomes in patients whose pheochromocytoma resection was performed either laparoscopically or by traditional open surgery., Methods: Fourteen consecutive patients who underwent laparoscopic procedures (a single surgeon) were compared with 20 patients who underwent open surgery. The patients' records were reviewed for demographic information, preoperative medical history and therapy, intraoperative hemodynamic data, fluid balance, and immediate postoperative course., Results: No differences between the highest intraoperative blood pressures and number of hypertensive episodes between the two groups were found. However, in laparoscopic patients, the intraoperative hypotension was less severe (mean lowest blood pressure 98/57 mm Hg versus 88/50 mm Hg, P = 0.05), and the hypotensive episodes were less frequent (median 0 versus 2, P = 0.005) and required fewer interventions with vasopressors (P = 0.02). Extreme high and extreme low heart rates did not differ between the two groups. The estimated blood loss was lower in the laparoscopic group (P = 0.0001), but the total intraoperative fluid requirement and operative times were similar in the two groups. Patients in the laparoscopic group resumed walking earlier (median 1.5 versus 4 days, P = 0.002) and resumed oral food intake sooner (median 1 versus 3.5 days, P = 0.0001). The median duration of hospitalization in patients who underwent laparoscopic and open adrenalectomy was 3 and 7.5 days, respectively (P = 0.001)., Conclusions: Intraoperative hemodynamic values during laparoscopic adrenalectomy for pheochromocytoma were comparable to those of traditional open surgery, but the patients who underwent the laparoscopic procedure had a faster postoperative recovery.

Purpose: Needlescopic adrenalectomy, partially incorporating 2 mm. instrumentation, is currently our preferred technique for transperitoneal endoscopic adrenalectomy. Although this minimally invasive technique results in decreased morbidity and shorter hospital stay, to our knowledge financial implications vis-à-vis open adrenalectomy have not been elucidated. We retrospectively compared the costs of needlescopic adrenalectomy to traditional open adrenalectomy., Materials and Methods: From September 1997 through March 1998, 15 patients underwent needlescopic adrenalectomy. Financial records of these patients were compared to those of 15 contemporary patients undergoing open adrenalectomy between January 1995 and May 1997. Adrenal pathology and tumor size were comparable between the 2 groups. Yearly costs were adjusted for inflation to 1998 dollars using a 4% annual rate. Needlescopic financial data are expressed as a ratio of open adrenalectomy costs, which are expressed as a unit of 1., Results: Overall, needlescopic adrenalectomy resulted in a 17.9% decrease in total hospital costs compared to open adrenalectomy. While the needlescopic approach was associated with an 18.1% increase in intraoperative costs, postoperative costs were 63.4% lower., Conclusions: These data demonstrate that in addition to providing a shorter hospital stay, decreased morbidity and quicker recovery, needlescopic adrenalectomy also is 17.9% less expensive than open adrenalectomy.

Background: No data are available on the long-term medical management of aldosterone-producing adenomas., Objective: To demonstrate the efficacy of medical management of aldosterone-producing adenomas in terms of blood pressure and serum potassium concentration and to discuss morbidity associated with medical management., Design: Retrospective cohort study., Setting: Large tertiary care referral center., Patients: 24 patients with documented aldosterone-producing adenomas who were treated medically for at least 5 years., Measurements: Aldosterone excretion rate, plasma renin activity, and size and location of adenomas (by computed tomography). Blood pressure and serum electrolytes were measured at the time of diagnosis and last follow-up., Results: From the time of diagnosis to the time of last follow-up, systolic blood pressure decreased from 175 mm Hg to 129 mm Hg (95% CI for difference, 37.1 to 53.8 mm Hg) and diastolic blood pressure decreased from 106 mm Hg to 79 mm Hg (CI for difference, 20.8 to 33.9 mm Hg). Serum potassium concentration increased from 3.0 mmol/L to 4.3 mmol/L (CI for difference, 1.1 to 1.5 mmol/L)., Conclusions: Medical management of aldosterone-producing adenomas is a viable option for controlling blood pressure and serum potassium concentration.

Purpose: We describe our experience with surgical management, complications and treatment outcome of histologically confirmed pheochromocytoma., Materials and Methods: The records of 113 patients who underwent surgical excision of pheochromocytoma were reviewed and assessed for preoperative medical treatment, intraoperative findings, postoperative hospitalization and complications., Results: There were no surgical mortalities. Average length of stay in the intensive care unit was 1.2 days. There were only 6 major cardiovascular complications all of which occurred in patients who received preoperative medications, including 5 with alpha blockade. Patients receiving no preoperative alpha blockade required an average of 956 cc less in total intraoperative fluids, which approached statistical significance, and 479 cc less fluids on postoperative day 1, which was statistically significant., Conclusions: Preoperative alpha-adrenergic blockade is not essential in pheochromocytoma patients. Calcium channel blockers are just as effective and safer when used as the primary mode of antihypertensive therapy. Surgery for pheochromocytoma is safe in the modern era.

Purpose: We compare the effectiveness and efficiency of laparoscopic adrenalectomy to open surgical management of adrenal disorders., Materials and Methods: A retrospective comparison was undertaken of 21 patients who underwent transperitoneal laparoscopic adrenalectomy between April 1996 and May 1997 with 17 patients who underwent open adrenalectomy between October 1994 and January 1996. Any patient suspected of having primary adrenal carcinoma and/or an adrenal lesion larger than 6 cm. was excluded from the study., Results: Patient demographics were matched well. Mean laparoscopic surgical time was 79 minutes longer than for open surgery. After overcoming the learning curve, the surgical time decreased by 59 minutes in the last 10 laparoscopic adrenalectomies. All laparoscopic intraoperative complications were managed without the need for open surgical conversion. Postoperative characteristics demonstrated significant benefits in the laparoscopic group (p=0.001) with respect to days to return to full diet (1.7 versus 4.6), analgesic pain requirements and days of hospitalization (2.7 versus 6.2)., Conclusions: Laparoscopic adrenalectomy offers significant postoperative benefits to patients with benign adrenal disease requiring surgical intervention. The surgical time is longer than that for open adrenalectomy but there was an encouraging reduction in time after overcoming the laparoscopic learning curve. Laparoscopic adrenalectomy is an excellent choice for tumors smaller than 6 cm. Its role for larger lesions and/or primary adrenal carcinoma is currently under investigation.

Objectives: To report the initial series of needlescopic transperitoneal adrenalectomy and to compare the results with a contemporary series of conventional transperitoneal laparoscopic adrenalectomy performed at the same institution., Methods: Fifteen patients underwent needlescopic adrenalectomy over a 4-month period. Outcome data were retrospectively compared with 21 conventional laparoscopic adrenalectomies performed over the preceding 12-month period at the same institution. The needlescopic technique included three subcostal ports (two, 2 mm; one, 5 mm) and one umbilical port for ultimate specimen extraction (10/12 mm). The laparoscopic technique included four subcostal ports (all 10/12 mm). Endoscopic transperitoneal adrenalectomy was completed by the standard technique in both groups., Results: Baseline demographics were comparable between the needlescopic (n = 15) and laparoscopic (n = 21) groups. The needlescopic group had a shorter surgical time (169 versus 220 minutes, P = 0.05), less blood loss (61 versus 183 mL, P = 0.002), and shorter hospital stay (1.1 versus 2.7 days, P < 0.001). Convalescence averaged 2.1 weeks in the needlescopic group and 3.1 weeks in the laparoscopic group (P < 0.001). No significant complications occurred in either group. One patient in the needlescopic group was converted to conventional laparoscopy because of marked obesity; hospital stay in this patient was 2 days., Conclusions: Reported herein is the initial series of needlescopic adrenalectomy. Compared with conventional laparoscopy, needlescopic adrenalectomy results in an overnight hospital stay, rapid recovery, and excellent cosmesis. However, prior experience with conventional laparoscopy is essential before embarking on needlescopic surgery.

Laparoscopic adrenalectomy by the transperitoneal route has been shown to be a safe and effective approach to select adrenal pathology. Although the specific indications will continue to be refined, it is clear that for adrenal masses of 6 cm or less, laparoscopy provides excellent access with little additional risk to the patient. In addition there appears to be an improved postoperative course when compared with open adrenalectomy. This latter point, however, requires careful prospective studies to confirm this impression objectively. The operative times are longer by the laparoscopic approach, but undoubtedly these times will decrease with increasing experience and improved laparoscopic instrumentation.

The role of nitric oxide (NO) in the regulation of aldosterone synthesis in the adrenal glomerulosa is not known. In this study, we observed that liberators of NO such as S-nitroso-N-acetyl-penicillamine (SNAP), sodium nitroprusside (Snp) and spermine nonoate (SNO) could significantly inhibit angiotensin II (AII) and ACTH-induced aldosterone synthesis in isolated rat and cultured human adrenal glomerulosa cells. To evaluate more precisely whether glomerulosa cells express NO synthase, we performed immunoblotting experiments with antibodies specific for the endothelial type ecNO synthase as well as the neuronal NO synthase. This revealed the presence of the ecNO synthase in rat adrenal capsules, in normal and in adenomatous human adrenal glomerulosa tissue, as well as in freshly dispersed rat adrenal glomerulosa cells. Furthermore, on immunohistochemical analysis, rat adrenal glomerulosa cell sections showed strongly positive staining for ecNO synthase. These results suggest that NO may be an important negative modulator of adrenal glomerulosa steroidogenesis.

Objectives: The cause of persistent hypertension following the removal of an aldosterone-producing adrenal adenoma is unknown. The purpose of this study was to determine whether this occurrence is due to existing renal histopathologic damage., Methods: Thirty-two patients with primary hyperaldosteronism due to an aldosterone-secreting adrenal cortical adenoma underwent open renal biopsy at the time of unilateral adrenalectomy. Biopsy results were correlated with the duration and severity of hypertension before and after surgery., Results: Nineteen patients were cured of their hypertension postoperatively, whereas 13 patients had persistent diastolic hypertension. Statistical analysis of these two groups revealed no difference when renal histopathologic variables, preoperative severity of hypertension, or preoperative duration of hypertension were compared., Conclusions: Persistent hypertension in these patients does not appear to be due to renal histopathologic changes; coexisting essential hypertension is a more likely cause.

Background: Congestive heart failure is associated with blood volume expansion caused by stimulation of the renin-aldosterone system and arginine vasopressin. The use of left ventricular assist devices as bridges to heart transplantation has improved the survival of patients during this critical period. In studying heart failure physiology on support devices, we hypothesized that improvement of cardiac function by a left ventricular assist device is associated with normalization of volume load secondary to normalization of its regulatory substances., Methods and Results: We studied 15 patients (13 men, 2 women: age 51 +/- 8 years) with end-stage heart failure who were cardiac transplant candidates eligible for HeartMate implantation. We measured plasma volume and plasma levels of atrial natriuretic peptide, aldosterone, renin, and arginine vasopressin sequentially before HeartMate implantation (baseline), after HeartMate implantation (weeks 4 and 8), and after transplantation. Baseline plasma volume was 123 +/- 20% of normal; it was 122 +/- 22% at week 4 and decreased to 115 +/- 14% at week 8. Atrial natriuretic peptide was 359 +/- 380 pg/mL at baseline, 245 +/- 175 pg/mL at week 4, and 151 +/- 66 pg/mL at week 8. Plasma aldosterone fell from 68 +/- 59 ng/dL at baseline to 17 +/- 16 ng/dL at week 4 (P < .05 versus baseline) and was 32 +/- 50 ng/dL at week 8. Plasma renin activity decreased from 80 +/- 88 ng/dL at baseline to 11 +/- 12 ng/dL at week 4 and was 16 +/- 38 ng/dL at week 8 (both P < .05 versus baseline). Arginine vasopressin fell from 5.0 +/- 4.8 fmol/mL at baseline to 1.1 +/- 0.7 fmol/mL at week 4 and 1.2+/-0.8 fmol/mL at week 8 (both P < .05 versus baseline)., Conclusions: The reduction of plasma renin activity, plasma aldosterone, and arginine vasopressin occurred earlier than the reduction of plasma volume and atrial natriuretic peptide after HeartMate implantation, possibly because of decreased pulmonary congestion and improved renal perfusion. The reduction of atrial natriuretic peptide cannot be responsible for the lack of adequate decrease of plasma volume; its reduction can be taken as a marker of improved cardiac pump function and decreased atrial stretch.

A case of a malignant pheochromocytoma arising from the anterior mediastinum is presented. We report the use of positron emission tomography with 82Rb and [18F]fluorodeoxyglucose to successfully image this neoplasm.

Neuropeptide Y (NPY) levels are increased in plasma and tumors of patients with pheochromocytoma. The present study was designed to evaluate plasma and tissue NPY levels simultaneously as well as to study its release and expression in patients with either adrenal or extraadrenal pheochromocytomas. Plasma NPY levels were higher (P < 0.01) in patients with adrenal tumors than in matched normal subjects and patients with extraadrenal tumors. NPY levels were also higher (P < 0.05) in adrenal than in extraadrenal tumors. Bioactive NPY (1-36) was the predominant form in plasma and tumors of patients with adrenal pheochromocytomas. In contrast, patients with extraadrenal pheochromocytomas had an abundance of NPY fragments. NPY mRNA was abundant in 11 of 13 adrenal tumors but in only 1 of 6 extraadrenal tumors. Moreover, NPY was coreleased with NE with manipulation of adrenal but not extraadrenal tumors. These findings indicate that increased NPY gene expression in adrenal pheochromocytomas accounts for the greater biosynthesis and storage of NPY in these tumors and that increased release of NPY results in elevated plasma NPY. Factors regulating NPY gene expression in pheochromocytoma and the role of NPY in the clinical manifestations of the disease remain to be elucidated.

Extra-adrenal paragangliomas (PGOMAs) are rare and can occur anywhere along the sympathetic chain including the carotid body, glomus jugulare, vagal bodies, ganglium tympanicum, larynx, ciliary bodies, organs of Zuckerkandl, urinary bladder, and other locations. These are microscopically identical. The embryological origin is from neural crest cells. One to three percent are reported to be functioning, predominantly secreting norepinephrine. Diagnosis of a functioning PGOMA can be delayed, even when symptoms of catecholamine hypersecretion are present. Furthermore, diagnostic testing and surgery have a significant morbidity if the diagnosis is not considered in advance, as illustrated by the following cases. PGOMAs can be sporadic or familial with an autosomal dominant pattern with variable penetrance. They can be multicentric and associated with other endocrine gland tumors. Benign and malignant PGOMAs have been described, with malignancy being defined by lymph node metastasis. Few cases of functioning glomus jugulare and carotid body tumors have been reported in the medical literature.

None of the endocrine causes for hypertension is more fascinating and challenging for the clinician than pheochromocytoma. Its protean manifestations can make diagnosis difficult, yet its sinister prognostic implications demand prompt recognition and expert management. Diagnosis depends on clinical suspicion, demonstration of high levels of free catecholamines in the plasma or urine, or high localization of the tumor by appropriate imaging techniques that include CT scanning, MR imaging, and 131I-MIBG scintigraphy. Surgical extirpation is the treatment of choice unless the risk of operation is overwhelming or distant metastasis has already occurred. Successful outcome demands a team approach, taking advantage of the experience, skill, and expertise of the surgeon, anesthesiologist, and internist.

The clinical manifestations of primary aldosteronism are not distinctive, but additional studies are warranted in certain hypertensive patients, including patients with either spontaneous or diuretic-induced hypokalemia and those with refractory hypertension without an obvious secondary cause. The best test for identifying patients with primary aldosteronism is measuring the aldosterone excretion rate during salt loading. A rate exceeding 14 micrograms/24 hour provides the highest sensitivity and specificity. The presence of hypokalemia and suppressed plasma renin activity provides corroborative evidence but their absence does not preclude the diagnosis. An adenoma is likely in the presence of significant spontaneous hypokalemia (serum potassium concentration < or = 3 mEq/L), a paradoxic decrease in ambulatory plasma aldosterone concentration, and plasma 18-hydroxycorticosterone values equal to or greater than 100 ng/dL. The adrenal CT scan should be considered the initial step in localization. Primary aldosteronism can be associated with severe and drug-resistant hypertension, and maintained hypervolemia is the reason for resistance to therapy. Sustained volume depletion is the most important therapeutic goal for these patients. Medical therapy is indicated for patients with hyperplasia and for patients with bilateral adenomas that may require total bilateral adrenalectomy. Whenever feasible, surgical excision is recommended for unilateral tumors, and cure can be achieved despite prolonged and severe hypertension.

We assessed the clinical utility of serum chromogranin A (CgA) alone and in combination with plasma catecholamines in the diagnosis of pheochromocytoma in patients with mild to moderate renal impairment. The study population consisted of 44 normal subjects, 50 subjects with proven pheochromocytoma, and 82 subjects with hypertension (60 primary and 22 secondary) suspected but not proven to have the disease. In this highly selected group with high disease prevalence (38%), the overall sensitivity, specificity, accuracy, and positive and negative predictive values of serum CgA in the diagnosis of pheochromocytoma were 86%, 74%, 79%, 67%, and 94%, respectively. However, in patients with creatinine clearance less than 1.33 mL/s (80 mL/min), these values dropped to 85%, 50%, 59%, 38%, and 90%, respectively. The combination of plasma catecholamines and CgA provided the best overall specificity (95%), accuracy (88%), and positive predictive value (91%). In patients with a creatinine clearance of more than 1.33 mL/s, the combination gave a specificity of 98%, an accuracy of 89%, and a positive predictive value of 97%. These results show that serum CgA has poor diagnostic specificity in the diagnosis of pheochromocytoma when renal function is impaired. Combining CgA with plasma catecholamines provides a lower sensitivity, but excellent specificity, accuracy, and positive predictive value.

The effects of fentanyl on ultrastructure, protein biosynthesis, and atrial natriuretic peptide (ANP) secretion were studied in neonatal rat cardiomyocytes (CM). Ventricles from 2-day-old American Wistar rats were digested with 1% collagenase in perfusion buffer. Eight hundred thousand to 1.0 million cells/ml were incubated in tissue culture media, to which fentanyl citrate (Sublimaze) was added in a dose of 10-50 ng/ml. Fentanyl increased the spontaneous CM beating rate, which became rather fibrillary in nature. Protein biosynthesis also increased in a time-related manner. Simultaneous incubation with naloxone (10(-6) M) did not alter the beating rate or protein synthesis. Ultrastructurally, several criteria of myocyte growth were observed: an increase in myofilaments and the appearance of newly formed organized sarcomeres, which were preceded by an increase in the ribosomes and cisternae of rough endoplasmic reticulum, and the appearance of large, adult-type mitochondria with increased matrix granules and long parallel cristae. The latter replaced the elongated thin fetal mitochondria. This was associated with a network of developing sarcoplasmic reticulum and T-tubular system as well as the formation of intercalated discs between the CM. Furthermore, exposure to fentanyl increased ANP immunoreactivity in the culture media while simultaneous incubation with naloxone blocked the effect of fentanyl on ANP secretion. On the other hand, naloxone alone did not alter ANP secretion. Therefore, it could be concluded that fentanyl stimulated protein biosynthesis and ANP secretion as evidenced both biochemically and ultrastructurally. Although the molecular mechanism of ANP secretion by fentanyl is still unclear, yet an opioid receptor mediation could be possible as ANP secretion was blocked by an opioid receptor antagonist (naloxone).

High levels of dietary calcium attenuate the elevation of arterial pressure induced by deoxycorticosterone (DOC)-salt in trained, conscious dogs. This response resulted primarily from the failure of the expected rise in peripheral vascular resistance to develop. In addition, the enhanced pressor sensitivity to norepinephrine and angiotensin II associated with DOC-salt hypertension was normalized by high levels of dietary calcium. These changes could not be explained by changes in serum potassium concentration, plasma catecholamines concentration, or plasma volume. A possible explanation is that high levels of dietary calcium inhibit a parathyroid hypertensive factor that has been observed to be elevated in mineralocorticoid-induced hypertension. This hypothesis requires further studies.